TFMPP is rarely used by itself. In fact, TFMPP reduces locomotor activity and produces aversive effects in animals rather than self-administration, which may explain the decision of the DEA not to permanently make TFMPP a controlled substance.[4] More commonly, TFMPP is co-administered with BZP, which acts as a norepinephrine and dopamine releasing agent.[6] Due to the serotonin agonist effects and increase in serotonin, norepinephrine, and dopamine levels produced by the BZP/TFMPP combination, this mixture of drugs produces effects which crudely mimic those of MDMA.[7]

The combination of BZP and TFMPP has been associated with a range of side effects, including insomnia, anxiety, nausea and vomiting, headaches and muscle aches which may resemble migraine, seizures, impotence, and rarely psychosis,[3] as well as a prolonged and unpleasant hangover effect. These side effects tend to be significantly worsened when the BZP/TFMPP mix is consumed alongside alcohol, especially the headache, nausea, and hangover.

However, it is difficult to say how many of these side effects are produced by TFMPP itself, as it has rarely been marketed without BZP also being present, and all of the side effects mentioned are also produced by BZP (which has been sold as a single drug). Studies into other related piperazine drugs such as mCPP suggest that certain side effects such as anxiety, headache and nausea are common to all drugs of this class, and pills containing TFMPP are reported by users to produce comparatively more severe hangover effects than those containing only BZP. The drug can also cause the body to tremble for a long period of time.[8][unreliable source?]

Since 2012, TFMPP has been listed as a Schedule III controlled substance in Canada,[9] making possession of TFMPP a federal offence. It has also been added to Part J of the Food and Drug Regulations thereby prohibiting the production, export or import of the substance.

Based on the recommendation of the EACD, the New Zealand government has passed legislation which placed BZP, along with the other piperazine derivatives TFMPP, mCPP, pFPP, MeOPP and MBZP, into Class C of the New Zealand Misuse of Drugs Act 1975. A ban was intended to come into effect in New Zealand on December 18, 2007, but the law change did not go through until the following year, and the sale of BZP and the other listed piperazines became illegal in New Zealand as of 1 April 2008. An amnesty for possession and usage of these drugs remained until October 2008, at which point they became completely illegal.[11]

TFMPP is not currently scheduled at the federal level in the United States,[13] but it was briefly emergency scheduled in Schedule I. The scheduling expired in April 2004 and was not renewed.[14] However, some states such as Florida have banned the drug in their criminal statutes making its possession a felony.[15]

1.
Regulation of therapeutic goods
–
The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc

2.
Misuse of Drugs Act 1975
–
The Misuse of Drugs Act 1975 is a New Zealand drug control law that classifies drugs into three classes, or schedules, based on their projected risk of serious harm of loss of life. The Controlled Substances Classification system has been around for decades but only in 2006 was benzylpiperazine was classified that a substance first became scheduled for health reasons. Most of the controlled substances, such as opium, cocaine. During this conference, the United States were strongly advocating for the banning of these substances unless a scientific or medical use became apparent. New Zealand signed this treaty and its 37th Parliament went on to incorporate this law into the Misuse of Drugs Act 1975, however, the United States did not sign the treaty. ^Note 2, Temazepam and flunitrazepam are subject to legal restrictions. The Expert Advisory Committee on Drugs makes scheduling decisions, based on scientific, national Drug Policy New Zealand notes, The Conventions place certain obligations on signatory countries. When the UN classifies a substance under one of the above Conventions, accordingly, the impetus for some of the drugs to be considered by the EACD will originate from decisions made at the UN

3.
PubChem
–
PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service

4.
ChemSpider
–
ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses

5.
Chemical formula
–
These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH

6.
International Chemical Identifier
–
Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure

7.
Recreational drug
–
Recreational drug use is the use of a psychoactive drug to alter ones mental state in a way that modifies emotions, perceptions, and feelings for recreational purposes. When a substance enters the body, it brings on an intoxicating effect. Generally, people use drugs that fall into three categories, depressants, stimulants, and psychedelic drugs. In popular usage, it is considered to be a tolerated social behaviour rather than a serious medical condition such as self-medication. The substances classified as controlled and illegal drugs vary by country, in 2009 it was estimated that about 3% to 6% of people aged 15 to 65 had used illegal drugs at least once. International and domestic law enforcement agencies are perpetually occupied with interdiction efforts against illegal use, manufacture. Many researchers have explored the etiology of recreational drug use, there has not been agreement around any one single cause. Instead, experts tend to apply the biopsychosocial model, any number of these factors are likely to influence an individual’s drug use as they are not mutually exclusive. Regardless of genetics, mental health or traumatic experiences, social factors play a role in exposure to and availability of certain types of drugs. According to addiction researcher Martin A. Plant, many go through a period of self-redefinition before initiating recreational drug use. They tend to view using drugs as part of a lifestyle that involves belonging to a subculture that they associate with heightened status. Plant says, “From the users point of there are many positive reasons to become part of the milieu of drug taking. The reasons for drug use appear to have as much to do with needs for friendship, pleasure, becoming a drug taker, to many people, is a positive affirmation rather than a negative experience. ”Anthropological research has suggested that humansmay have evolved to counter-exploit plant neurotoxins. The ability to use chemicals to serve the function of endogenous neurotransmitters may have improved survival rates. A typically restrictive prehistoric diet may have emphasised the apparent benefit of consuming psychoactive drugs, severity and type of risks that come with recreational drug use vary widely with the drug in question and the amount being used. There are many factors in the environment and within the user interact with each drug differently. Overall, some studies suggest that alcohol is one of the most dangerous of all drugs, only heroin, crack cocaine. Researcher David Nutt stated that studies showing benefits for moderate alcohol consumption lacked control for the variable of what the subjects were drinking

8.
Piperazine
–
Piperazine is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste, the piperazines are a broad class of chemical compounds, many with important pharmacological properties, which contain a core piperazine functional group. Piperazines were originally named because of their similarity with piperidine. It is important to note, however, that piperazines are not derived from plants in the Piper genus, piperazine is freely soluble in water and ethylene glycol, but insoluble in diethyl ether. It is a base with two pKbs of 5.35 and 9.73 at 25 °C. the pH of a 10% aqueous solution of piperazine is 10. 8-11.8. Piperazine readily absorbs water and carbon dioxide from the air, a form in which piperazine is commonly available industrially is as the hexahydrate, C4H10N2. 6H2O, which melts at 44 °C and boils at 125-130 °C, two common salts in the form of which piperazine is usually prepared for pharmaceutical or veterinary purposes are the citrate, 3C4H10N2. 2C6H8O7, and the adipate, C4H10N2. C6H10O4. Piperazine is formed as a co-product in the ammoniation of 1 and these are the only routes to the chemical used commercially. The piperazine is separated from the stream, which contains ethylenediamine, diethylenetriamine. Piperazine was first introduced as an anthelmintic in 1953, a large number of piperazine compounds have anthelmintic action. Their mode of action is generally by paralysing parasites, which allows the host body to remove or expel the invading organism. The neuromuscular effects are thought to be caused by blocking acetylcholine at the myoneural junction and this action is mediated by its agonist effects upon the inhibitory GABA receptor. Its selectivity for helminths is because vertebrates only use GABA in the CNS, piperazine hydrate, piperazine adipate and piperazine citrate are the most common anthelmintic piperazine compounds. These drugs are referred to simply as piperazine which may cause confusion between the specific anthelmintic drugs, the entire class of piperazine-containing compounds, and the compound itself. Diethylcarbamazine, a derivative of piperazine, is used to some types of filariasis. Piperazines are also used in the manufacture of plastics, resins, pesticides, brake fluid, piperazines, especially BZP and TFMPP were extremely common adulterants in the club and rave scene, often being passed off as MDMA, although they do not share many similarities in their effects. Piperazine is also a used for CO2 and H2S scrubbing in association with methyl diethanolamine. The thermal degradation rates for methyl diethanolamine and piperazine are negligible and this increased stability of the MDEA/PZ solvent blend over MDEA and other amine solvents provides for greater capacity for and requires less work to capture a given amount of CO2

9.
Structural analog
–
It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analog can be imagined to be formed, at least theoretically, despite a high chemical similarity, structural analogs are not necessarily functional analogs and can have very different physical, chemical, biochemical, or pharmacological properties. Chemical analogues of illegal drugs are developed and sold in order to circumvent laws, such substances are often called designer drugs. Because of this, the United States passed the Federal Analog Act in 1986 and this bill banned the production of any chemical analogue of a Schedule I or Schedule II substance that has substantially similar pharmacological effects, with the intent of human consumption

10.
Benzylpiperazine
–
Benzylpiperazine is a recreational drug with euphoriant and stimulant properties. The effects produced by BZP are comparable to those produced by amphetamine, adverse effects have been reported following its use including acute psychosis, renal toxicity and seizures. No deaths have been reported following a sole ingestion of BZP and its sale is banned in several countries, including Australia, Canada, New Zealand, the United States, the Republic of Ireland, the United Kingdom, Bulgaria, Romania and other parts of Europe. It is often claimed that BZP was originally synthesized as a potential agent for use in farm animals. However, there are references to BZP in medical literature that predate interest in piperazines as antihelminthics. It was discovered that BZP had side effects and was abandoned as a worm treatment. The study suggested that BZP “should be placed under statutory control similar to those regulating the use of amphetamine. ”In the early 1990s and it also reported that BZP was being used as an adulterant in illicit drugs. Not long after, there was an explosion in the drugs use worldwide – a situation which was followed by legislative control in many countries. Since 1999, benzylpiperazine use grew sharply in New Zealand due to a complete lack of regulation. The New Zealand government attempted to ban the product as of 18 December 2007 and it was so widely used that an estimated 5 million pills were sold in New Zealand in 2007. Piperazine-based stimulants began to appear in Europe in 2000 but remained unavailable in the rest of the world until recently. As of May 2008 piperazines such as BZP and TFMPP have been under evaluation by Health Canada in order to determine whether or not party-pills pose a significant health risk to individuals. At this time no official decision has made regarding these specific piperazines becoming restricted substances. In the United States, it is used as an adulterant in ecstasy mimic tablets. BZP is a derivative which comes as either the hydrochloride salt or a free base. The hydrochloride salt is a white solid while the form is a slightly yellowish-green liquid. BZP base is corrosive and causes burns, in countries where its purchase is legal, BZP products are often produced in small specialist laboratories. The raw materials can be purchased from various chemical supply agencies, the resulting product can be marketed at extremely high markup, so end-user prices can be as high as 300 times the bulk cost of raw ingredients

11.
MDMA
–
3, 4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a psychoactive drug used primarily as a recreational drug. Desired effects include increased empathy, euphoria, and heightened sensations, when taken by mouth, effects begin after 30–45 minutes and last 3–6 hours. It is also sometimes snorted or smoked, as of 2017, MDMA has no accepted medical uses. Adverse effects of MDMA use include addiction, memory problems, paranoia, difficulty sleeping, teeth grinding, blurred vision, sweating, use may also lead to depression and fatigue. Deaths have been reported due to increased temperature and dehydration. MDMA increases the release and slows the reuptake of the serotonin, dopamine. It has stimulant and psychedelic effects, the initial increase is followed by a short-term decrease in the neurotransmitters. MDMA belongs to the substituted methylenedioxyphenethylamine and substituted amphetamine classes of drugs, MDMA was first made in 1912. It was used to improve psychotherapy beginning in the 1970s and became popular as a drug in the 1980s. MDMA is commonly associated with parties, raves, and electronic dance music. It is often mixed with other substances such as ephedrine, amphetamine. In 2014, between 9 and 29 million people between the ages of 15 and 64 used ecstasy and this was broadly similar to the percentage of people who use cocaine, amphetamines, and opioids, but fewer than for cannabis. In the United States, about 0.9 million people used ecstasy in 2010, MDMA is generally illegal in most countries. Limited exceptions are made for research. Researchers are investigating whether a few low doses of MDMA may assist in treating severe, in November 2016, phase 3 clinical trials for PTSD were approved by the United States Food and Drug Administration to assess effectiveness and safety. As of 2017, MDMA has no accepted medical indications, before it was widely banned, it saw limited use in therapy. A small number of therapists continue to use MDMA in therapy despite its illegal status, MDMA is often considered the drug of choice within the rave culture and is also used at clubs, festivals and house parties. In the rave environment, the effects from the music

12.
Affinity (pharmacology)
–
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein, the binding typically results in a change of conformation of the target protein. In DNA-ligand binding studies, the ligand can be a molecule, ion. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure, the instance of binding occurs over an infinitesimal range of time and space, so the rate constant is usually a very small number. Binding occurs by intermolecular forces, such as bonds, hydrogen bonds. The association of docking is actually reversible through dissociation, measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry, in biochemistry it is whether the ligand generally binds at a metal site. In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed, the etymology stems from ligare, which means to bind. Ligand binding to a receptor protein alters the chemical conformation by affecting the shape orientation. The conformation of a receptor protein composes the functional state, ligands include substrates, inhibitors, activators, and neurotransmitters. The rate of binding is called affinity, and this measurement typifies a tendency or strength of the effect, binding affinity is actualized not only by host-guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution. The solvent provides an environment for the ligand and receptor to adapt. Radioligands are radioisotope labeled compounds are used in vivo as tracers in PET studies, the interaction of most ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity binding results in a degree of occupancy for the ligand at its receptor binding site than is the case for low-affinity binding. A ligand that can bind to a receptor, alter the function of the receptor, high-affinity ligand binding implies that a relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. The lower the Ki concentration is, the more likely there will be a reaction between the pending ion and the receptive antigen. In the example shown to the right, two different ligands bind to the receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, an agonist that can only partially activate the physiological response is called a partial agonist

13.
5-HT1A
–
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin. It is a G protein-coupled receptor that is coupled to Gi/Go, HTR1A denotes the human gene encoding for the receptor. The 5-HT1A receptor is the most widespread of all the 5-HT receptors, the 5-HT1A receptors in the raphe nucleus are largely somatodendritic autoreceptors, whereas those in other areas such as the hippocampus are postsynaptic receptors. 5-HT1A receptor agonists are involved in neuromodulation and they decrease blood pressure and heart rate via a central mechanism, by inducing peripheral vasodilation, and by stimulating the vagus nerve. These effects are the result of activation of 5-HT1A receptors within the ventrolateral medulla. Vasodilation of the vessels in the skin via central 5-HT1A activation increases heat dissipation from the organism out into the environment. Others such as gepirone, flesinoxan, flibanserin, and naluzotan have also been investigated, 5-HT1A receptor activation likely plays a significant role in the positive effects of serotonin releasing agents like MDMA as well. 5-HT1A receptors in the raphe nucleus are co-localized with neurokinin 1 receptors and have been shown to inhibit the release of substance P. Consequently, novel NK1 receptor antagonists are now in use for the treatment of nausea and emesis, as mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy. Enhancement of dopamine release in these areas may also play a role in the antidepressant. Activation of 5-HT1A receptors has been demonstrated to impair certain aspects of memory and learning, by inhibiting the release of glutamate, 5-HT1A activation are known to improve cognitive functions associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release. The receptor does not affect vasopressin or renin secretion, unlike the 5-HT2 receptors and it has been suggested that oxytocin release may contribute to the prosocial, antiaggressive, and anxiolytic properties observed upon activation of the receptor. β-Endorphin secretion may contribute to antidepressant, anxiolytic, and analgesic effects, 5-HT1A receptors can be located on the cell body, dendrites, axons, and both presynaptically and postsynaptically in nerve terminals or synapses. Those located on the soma and dendrites are referred to as somatodendritic, stimulation of 5-HT1A autoreceptors inhibits the release of serotonin in nerve terminals. This autoreceptor-mediated inhibition of serotonin release has been theorized to be a factor in the therapeutic lag that is seen with serotonergic antidepressants such as the SSRIs. The autoreceptors must first densensitize before the concentration of serotonin in the synapse can become elevated appreciably. Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as fenfluramine and MDMA bypass serotonin autoreceptors such as 5-HT1A. They do this by acting on the release mechanisms of serotonin neurons

14.
5-HT1B
–
5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype, 5-HT1B receptors are widely distributed throughout the CNS with the highest concentrations found in the frontal cortex, basal ganglia, striatum, and the hippocampus. The function of the 5-HT1B receptor differs depending upon its location, in the frontal cortex, it is believed to act as a postsynaptic receptor inhibiting the release of dopamine. In the hippocampus, a recent study has demonstrated that activation of postsynaptic 5-HT1B heteroreceptors produces a facilitation in excitatory synaptic transmission which is altered in depression. When the expression of 5-HT1B in human cortex was traced throughout life, significant changes during adolescence were observed, outside the brain, 5-HT1B receptor activation also has vascular effects, such as pulmonary vasoconstriction. Furthermore, blocking 5-HT1B receptor signalling increases the number of osteoblasts, bone mass, knockout mice lacking the 5-HT1B gene have shown an increase in aggression and a higher preference for alcohol. Under basal conditions, knockout mice present with a normal phenotype, however, after undergoing chronic unpredictable stress treatment to induce a depression-like phenotype these animals do not benefit from administration of selective serotonin reuptake inhibitor. A genetic variant in the region, A-161T, has been examined with respect to personality traits. IUPHAR Database of Receptors and Ion Channels, international Union of Basic and Clinical Pharmacology. Human HTR1B genome location and HTR1B gene details page in the UCSC Genome Browser and this article incorporates text from the United States National Library of Medicine, which is in the public domain

15.
5-HT1D
–
5-hydroxytryptamine receptor 1D, also known as HTR1D, is a 5-HT receptor, but also denotes the human gene encoding it. 5-HT1D acts on the nervous system, and affects locomotion. It also induces vascular vasoconstriction in the brain, 5HT1D receptor is a G protein linked receptor that activates an intracellular messenger cascade to produce an inhibitory response by decreasing cellular levels of cAMP. The 5HT1D is a 7-TM receptor, a large intercellular loop between TM-5 and TM-6 is believed to be associated with coupling to a second messenger. Agonists might bind in a manner that utilizes an aspartate residue in TM-3 and residues in the TM-4, TM-5, a human clone containing an intronless open reading frame was found to encode 377 amino acids of the 5HT1D receptor. The gene has been localized on chromosome 1, region 1p34. 3-36.3 Molecular modelling has provided a picture of the binding site of 5HT1D. The amino acid residues within the binding site region have been identified. This is a guide to design potential 5HT1D receptor agonists. When sumatriptan binds there is major conformational change in both ligand and receptor in the binding pocket, IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology, human HTR1D genome location and HTR1D gene details page in the UCSC Genome Browser. This article incorporates text from the United States National Library of Medicine, which is in the public domain

16.
5-HT2A
–
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an effect on certain areas such as the visual cortex. This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD, later it came back to prominence because it was also found to be mediating, at least partly, the action of many antipsychotic drugs, especially the atypical ones. 5-HT2A may be a receptor for the spread of the human polyoma virus called JC virus. Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors, deceased suicidal and otherwise depressed patients have had more 5-HT2A receptors than normal patients. These findings suggest that post-synaptic 5-HT2A overdensity is involved in the pathogenesis of depression, 5-HT2A is thought to correspond to what was originally described as D subtype of 5-HT receptors by Gaddum and Picarelli. Later it was shown that the 5-HT2 was very close to 5-HT1C and thus were clubbed together, thus the 5-HT2 receptor family is composed of three separate molecular entities, the 5-HT2A, the 5-HT2B and the 5-HT2C receptors. 5-HT2A is expressed throughout the central nervous system. It is expressed near most of the serotoninergic terminal rich areas, including neocortex, in the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer, and in the Purkinje cells. In the periphery, it is expressed in platelets and many cell types of the cardiovascular system, in fibroblasts. Additionally, 5-HT2A mRNA expression has been observed in human monocytes, the 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways, Gαq stimulates phospholipase C activity, which subsequently promotes the release of diacylglycerol and inositol triphosphate, which in turn stimulate protein kinase C activity and Ca2+ release. Other 5-HT2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced inflammation, activation of the 5-HT2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched, agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT2A–mGlu2, agonists enhance dopamine in PFC, enhances memory and plays an active role in attention and learning. O-4310, 5-HT2A selective, claimed to have 100x selectivity over 5-HT2C and be inactive at 5-HT2B PHA-57378, dual 5-HT2A / 5-HT2C agonist, anxiolytic effects in animal studies. 25C-NBOMe Methysergide, a congener of methylergonovine, used in treatment of migraine blocks 5-HT2A and 5-HT2C receptors, oSU-6162 acts as a partial agonist at both 5-HT2A and dopamine D2 receptors 25CN-NBOH, 100x selectivity for 5-HT2A over 5-HT2C, 46x selectivity over 5-HT2B. Efavirenz, a drug, produces psychiatric side effects thought to be mediated by 5-HT2A

17.
5-HT2C
–
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin. It is a G protein-coupled receptor that is coupled to Gq/G11, HTR2C denotes the human gene encoding for the receptor, that in humans is located at the X chromosome. As males have one copy of the gene and in one of the two copies of the gene is repressed, polymorphisms at this receptor can affect the two sexes to differing extent. At the cell surface the receptor exists as a homodimer, 5-HT2C receptors are widely distributed across the periphery and brain in humans. The 5-HT2C receptor is one of the binding sites for serotonin. Activation of this receptor by serotonin inhibits dopamine and norepinephrine release in areas of the brain. 5-HT2C receptors are claimed to significantly regulate mood, anxiety, feeding, 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others. Research indicates that some victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT2C antagonist, is an effective antidepressant, antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Many atypical antipsychotics block 5-HT2C receptors, but their use is limited by multiple undesirable actions on various neurotransmitters and receptors. Fluoxetine acts as a direct 5-HT2C antagonist in addition to inhibiting serotonin reuptake, however, an overactivity of 5-HT2C receptors may contribute to depressive and anxiety symptoms in a certain population of patients. Activation of 5-HT2C by serotonin is responsible for many of the side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine. Some of the anxiety caused by SSRIs is due to excessive signalling at 5-HT2C. Over a period of 1–2 weeks, the receptor begins to downregulate, along with the downregulation of 5-HT2A, 5-HT1A and this downregulation parallels the onset of the clinical benefits of SSRIs. 5-HT2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy, thus, 5-HT2C receptors do not require binding by a ligand in order to exhibit influence on neurotransmission. Inverse agonists may be required to fully extinguish 5-HT2C constitutive activity, 5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs, including caffeine, nicotine, amphetamine, morphine, cocaine, and others. 5-HT2C antagonism increases dopamine release in response to reinforcing drugs, feeding, social interaction, and sexual activity all release dopamine subject to inhibition of 5-HT2C. Increased 5-HT2C expression reduces dopamine release in both the presence and absence of stimuli, conditions that increase cytokine levels in the human body may have potential to raise 5-HT2C gene expression in the brain

18.
Receptor (biochemistry)
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In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, however, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels. Receptor proteins can be classified by their location, transmembrane receptors include ion channel-linked receptors, G protein-linked hormone receptors, and enzyme-linked hormone receptors. Intracellular receptors are found inside the cell, and include cytoplasmic receptors. The endogenously designated -molecule for a receptor is referred to as its endogenous ligand. E. g. the endogenous ligand for the acetylcholine receptor is acetylcholine but the receptor can also be activated by nicotine. Each receptor is linked to a specific cellular biochemical pathway, while numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure, much like how locks will only accept specifically shaped keys. When a ligand binds to its receptor, it activates or inhibits the receptors associated biochemical pathway. The ligand-binding cavities are located at the interface between the subunits, type 2, G protein-coupled receptors – This is the largest family of receptors and includes the receptors for several hormones and slow transmitters e. g. dopamine, metabotropic glutamate. They are composed of seven transmembrane alpha helices, the loops connecting the alpha helices form extracellular and intracellular domains. The aforementioned receptors are coupled to different intracellular effector systems via G proteins, the insulin receptor is an example. Type 4, Nuclear receptors – While they are called nuclear receptors, they are located in the cytoplasm. They are composed of a C-terminal ligand-binding region, a core DNA-binding domain, the core region has two zinc fingers that are responsible for recognizing the DNA sequences specific to this receptor. The N terminus interacts with other transcription factors in a ligand-independent manner. Steroid and thyroid-hormone receptors are examples of such receptors, membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents, detergents, and/or affinity purification. The structures and actions of receptors may be studied by using methods such as X-ray crystallography, NMR, circular dichroism. Computer simulations of the behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process, ligands bind to receptors and dissociate from them according to the law of mass action

19.
Full agonist
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An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, receptors can be activated by either endogenous or exogenous agonists, resulting in a biological response. A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor, an endogenous agonist for a particular receptor is a compound naturally produced by the body that binds to and activates that receptor. For example, the endogenous agonist for serotonin receptors is serotonin, a superagonist is a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%. Full agonists bind and activate a receptor, producing full efficacy at that receptor, one example of a drug that acts as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the nervous system. Partial agonists also bind and activate a receptor, but have only partial efficacy at the receptor relative to a full agonist. Agents like buprenorphine are used to treat opiate dependence for this reason, as they produce milder effects on the receptor with lower dependence. An inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor, inverse agonists exert the opposite pharmacological effect of a receptor agonist, not merely an absence of the agonist effect as seen with antagonist. An example is the inverse agonist rimonabant. A co-agonist works with other co-agonists to produce the desired effect together, NMDA receptor activation requires the binding of both glutamate, glycine and D-serine co-agonists. An irreversible agonist is a type of agonist that binds permanently to a receptor through the formation of covalent bonds, a few of these have been described. A selective agonist is selective for a type of receptor. E. g. buspirone is a selective agonist for serotonin 5-HT1A, terms that describe this phenomenon are functional selectivity, protean agonism, or selective receptor modulators. Potency is the amount of agonist needed to elicit a desired response, the potency of an agonist is inversely related to its EC50 value. The EC50 can be measured for a given agonist by determining the concentration of agonist needed to elicit half of the biological response of the agonist. The EC50 value is useful for comparing the potency of drugs with similar efficacies producing physiologically similar effects, the smaller the EC50 value, the greater the potency of the agonist, the lower the concentration of drug that is required to elicit the maximum biological response. This relationship, termed the index, is defined as the ratio TD50, ED50

20.
Receptor antagonist
–
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor. They are sometimes called blockers, examples include alpha blockers, beta blockers, antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors, biochemical receptors are large protein molecules that can be activated by the binding of a ligand. Receptors can be membrane-bound, occurring on the membrane, or intracellular. Binding occurs as a result of noncovalent interaction between the receptor and its ligand, at locations called the site on the receptor. A receptor may contain one or more binding sites for different ligands, binding to the active site on the receptor regulates receptor activation directly. The activity of receptors can also be regulated by the binding of a ligand to other sites on the receptor, antagonists mediate their effects through receptor interactions by preventing agonist-induced responses. This may be accomplished by binding to the site or the allosteric site. In addition, antagonists may interact at unique binding sites not normally involved in the regulation of the receptors activity to exert their effects. The term antagonist was originally coined to describe different profiles of drug effects, the biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s. The current accepted definition of receptor antagonist is based on the receptor occupancy model and it narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn on a cellular response by binding to the receptor. Antagonists were thought to turn off that response by blocking the receptor from the agonist and this definition also remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. Our understanding of the mechanism of drug-induced receptor activation and receptor theory, the two-state model of receptor activation has given way to multistate models with intermediate conformational states. This means efficacy may actually depend on where that receptor is expressed, by definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor, once bound, however, antagonists inhibit the function of agonists, inverse agonists, and partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist, the potency of an antagonist is usually defined by its half maximal inhibitory concentration IC50 value. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the biological response of an agonist

21.
Meta-chlorophenylpiperazine
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Meta-Chlorophenylpiperazine is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as ecstasy in Europe, despite its advertisement as a recreational substance, mCPP is actually generally considered to be an unpleasant experience and is not desired by drug users. It lacks any reinforcing effects, produces depressive and anxiogenic effects in rodents and humans and it also worsens obsessive-compulsive symptoms in people with the disorder. MCPP is known to induce headaches in humans and has used for testing potential antimigraine medications. It has potent anorectic effects and has encouraged the development of selective 5-HT2C receptor agonists for the treatment of obesity as well. MCPP possesses significant affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and it also has some affinity for α1-adrenergic, α2-adrenergic, H1, I1, and NET. It behaves as an agonist at most or all serotonin receptors, MCPP has been shown to act not only as a reuptake inhibitor of serotonin but as a releasing agent as well. MCPPs strongest actions are at the 5-HT2B and 5-HT2C receptors and its discriminative cue is mediated primarily by 5-HT2C, however, there is also evidence for mCPP antagonism of the 5-HT2A receptor, suggesting an indirect mechanism for the drugs psychedelic effects. Other effects of mCPP include nausea, hypoactivity, and penile erection, MCPP is metabolized via the CYP2D6 isoenzyme by hydroxylation to p-hydroxy-mCPP. Caution should be exercised in coprescribing inhibitors or substrates of CYP2D6 with drugs such as trazodone and nefazodone that have mCPP as a metabolite, as of October 2015 mCPP is a controlled substance in China. MCPP is legal in the Czech Republic, MCPP is illegal in Hungary since 2012. MCPP is illegal in Japan since 2006, MCPP is not illegal in the Netherlands. An amnesty for possession and usage of these remained until October 2008. However, it is important to note that mCPP is legally used for scientific research, chlorophenylpiperazine is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida. Quipazine - A related piperazine serotonin agonist

22.
5-HT3
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This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium, potassium, and calcium ions. Binding of the neurotransmitter 5-hydroxytryptamine to the 5-HT3 receptor opens the channel, the rapidly activating, desensitizing, inward current is predominantly carried by sodium and potassium ions. 5-HT3 receptors have a negligible permeability to anions and they are most closely related by homology to the nicotinic acetylcholine receptor. The 5-HT3 receptor differs markedly in structure and mechanism from the other 5-HT receptor subtypes, a functional channel may be composed of five identical 5-HT3A subunits or a mixture of 5-HT3A and one of the other four 5-HT3B, 5-HT3C, 5-HT3D, or 5-HT3E subunits. It appears that only the 5-HT3A subunits form functional homopentameric channels, all other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, and the homomeric 5-HT3A receptor, the subunits surround a central ion channel in a pseudo-symmetric manner. The 5-HT3 receptor gene is located on human chromosomal region 11q23. 1-q23.2 and it is similar in structure to the mouse gene which has 9 exons and is spread over ~13 kb. Interestingly, four of its introns are exactly in the position as the introns in the homologous α7-Acetylcholine receptor gene. Genes that code for the subunits of the 5-HT3 receptor have been identified, HTR3A and HTR3B for the 5-HT3A and 5-HT3B subunits and in addition HTR3C, HTR3D and HTR3E genes encoding 5-HT3C, 5-HT3D and 5-HT3E subunits. The latter three tend to show peripherally restricted pattern of expression, with levels in the gut. In human duodenum and stomach, for example, 5-HT3C and 5-HT3E mRNA might be greater than for 5-HT3A, there is some evidence to suggest that the 5-HT3 receptor subunits are an important contribution to the effectiveness of these compounds. In patients treated with drugs, certain polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the 5-HT3B receptor subunit could be used as biomarker of drug efficacy. HTR3C and HTR3E do not seem to form functional homomeric channels, the pathophysiological role for these additional subunits has yet to be identified. The 5-HT3 receptor is expressed throughout the central and peripheral nervous systems, 5-HT3 receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release, 5-HT1 receptor 5-HT2 receptor 5-HT4 receptor 5-HT5 receptor 5-HT6 receptor 5-HT7 receptor 5-HT3 Receptor at the US National Library of Medicine Medical Subject Headings

23.
Serotonin transporter
–
The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of transporter protein that transports serotonin from the synaptic cleft to the presynaptic neuron. This transport of serotonin by the SERT protein terminates the action of serotonin and this protein is the target of many antidepressant medications of the SSRI and Tricyclic antidepressant classes. It is a member of the sodium, neurotransmitter symporter family, serotonin-Reuptake transporters are dependent on both the concentration of potassium ion in the cytoplasm and the concentrations of sodium and chloride ions in the extracellular fluid. In order to function properly the Serotonin Transporter requires the potential created by the sodium-potassium adenosine triphosphatase. Right after the release of the Serotonin in the cytoplasm a potassium ion binds to the transporter which is now able to back out returning to its active state. The serotonin transporter removes serotonin from the synaptic cleft back into the synaptic boutons, thus, it terminates the effects of serotonin and simultaneously enables its reuse by the presynaptic neuron. Neurons communicate by using chemical messengers like serotonin between cells, the transporter protein, by recycling serotonin, regulates its concentration in a gap, or synapse, and thus its effects on a receiving neuron’s receptors. The serotonin transporter is also present in platelets, there, serotonin functions as a vasoconstrictive substance and it also serves as a signalling molecule to induce platelet aggregation. SERT spans the plasma membrane 12 times and it belongs to NE, DA, SERT monoamine transporter family. Transporters are important sites for agents that treat psychiatric disorders, drugs that reduce the binding of serotonin to transporters are used to treat mental disorders. The SSRI Fluoxetine and the Tricyclic antidepressant Clomipramine are examples of serotonin reuptake inhibitors, however, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhbitors bind to the central binding site overlapping the substrate binding site. Isosteres 3-cis-indole 8a, Ki =220 pM The gene that encodes the serotonin transporter is called solute carrier family 6, in humans the gene is found on chromosome 17 on location 17q11. 1–q12. These phenotypic changes may, e. g. be increased anxiety, the short variation has 14 repeats of a sequence while the long variation has 16 repeats. The short variation leads to less transcription for SLC6A4, and it has found that it can partly account for anxiety-related personality traits. This polymorphism has been investigated in over 300 scientific studies. The 5-HTTLPR polymorphism may be subdivided further, One study published in 2000 found 14 allelic variants in a group of around 200 Japanese and Caucasian people. In addition to altering the expression of SERT protein and concentrations of serotonin in the brain

24.
Releasing agent
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Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e. g. trace amines, many substituted amphetamines, and related compounds. MRAS can be classified by the monoamines they mainly release, although these drugs like on a spectrum and they may enter the presynaptic neuron primarily via plasma membrane transporters, such as the dopamine transporter, norepinephrine transporter, and serotonin transporter. Some, such as exogenous phenethylamine, amphetamine, and methamphetamine, certain MRAs interact with other presynaptic intracellular receptors which promote monoamine neurotransmission as well. Dopamine release agents, usually selective for norepinephrine and dopamine have psychostimulant effect, causing an increase in energy, and elevated mood. Other variables can significantly affect the effects, such as infusion rate. Selectively noradrenergic drugs are minimally psychoactive, but as demonstrated by ephedrine may be distinguished from placebo and they may also be ergogenic, in contrast to solely reuptake inhibitor reboxetine. MRAs act to varying extents on serotonin, norepinephrine, and dopamine, some induce the release of all three neurotransmitters to a similar degree, like MDMA, while others are more selective. As examples, amphetamine and methamphetamine are NDRAs but only very weak releasers of serotonin and MBDB is a fairly balanced SNRA, even more selective include agents like fenfluramine, a selective SRA, and ephedrine, a selective NRA. As of present, no selective DRAs are known and this is because it has proven extremely difficult to separate DAT affinity from NET affinity and retain releasing efficacy at the same time. Several selective SDRAs are known however, though these also act as non-selective serotonin receptor agonists. Monoamine reuptake inhibitor Release modulator Baumann MH, Mario AA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, the Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue. Iversen L, Gibbons S, Treble R, Setola V, Huang XP, neurochemical profiles of some novel psychoactive substances

25.
Serotonin
–
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is found in the gastrointestinal tract, blood platelets. It is popularly thought to be a contributor to feelings of well-being, approximately 90% of the human bodys total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions and these include the regulation of mood, appetite, and sleep. Serotonin also has some functions, including memory and learning. Modulation of serotonin at synapses is thought to be an action of several classes of pharmacological antidepressants. Serotonin secreted from the cells eventually finds its way out of tissues into the blood. There, it is taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver, metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the acetic acid derivative. The latter is then excreted by the kidneys, in addition to animals, serotonin is found in fungi and plants. Serotonins presence in insect venoms and plant spines serves to cause pain, Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds, Serotonin is a neurotransmitter and is found in all bilateral animals, where it mediates gut movements and the animals perceptions of resource availability. In less complex animals, such as invertebrates, resources simply mean food availability. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance, in response to the perceived abundance or scarcity of resources, an animals growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal, except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors that activate an intracellular second messenger cascade. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse and this is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron

26.
Dopamine
–
Dopamine is an organic chemical of the catecholamine and phenethylamine families that plays several important roles in the brain and body. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, dopamine is also synthesized in plants and most multicellular animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to nerve cells. The brain includes several distinct dopamine pathways, one of plays a major role in reward-motivated behavior. Most types of rewards increase the level of dopamine in the brain, other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a system which is neuromodulatory. Outside the central system, dopamine functions primarily as a local chemical messenger. With the exception of the vessels, dopamine in each of these peripheral systems is synthesized locally. Several important diseases of the system are associated with dysfunctions of the dopamine system. Parkinsons disease, a condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Its metabolic precursor L-DOPA can be manufactured, and in its pure form marketed as Levodopa is the most widely used treatment for the condition. There is evidence that schizophrenia involves altered levels of dopamine activity, similar dopamine antagonist drugs are also some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder are associated with decreased dopamine activity, dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. A dopamine molecule consists of a structure with one amine group attached via an ethyl chain. As such, dopamine is the simplest possible catecholamine, a family that includes the neurotransmitters norepinephrine and epinephrine. The presence of a ring with this amine attachment makes it a substituted phenethylamine. Like most amines, dopamine is an organic base, as a base, it is generally protonated in acidic environments. The protonated form is highly water-soluble and relatively stable, but can become oxidized if exposed to oxygen or other oxidants, in basic environments, dopamine is not protonated

27.
Norepinephrine
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Norepinephrine, also called noradrenaline or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone and neurotransmitter. Norepinephrine is also the international nonproprietary name given to the drug, regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic. In the brain, norepinephrine is produced in closely packed brain cell neurons or nuclei that are small yet exert powerful effects on brain areas. The most important of these nuclei is the locus coeruleus, located in the pons, regardless of how and where it is released, norepinephrine acts on target cells by binding to and activating noradrenergic receptors located on the cell surface. The general function of norepinephrine is to mobilize the brain and body for action, norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, a variety of medically important drugs work by altering the actions of norepinephrine systems. Norepinephrine itself is used as an injectable drug for the treatment of critically low blood pressure. Beta blockers, which some of the effects of norepinephrine, are frequently used to treat glaucoma, migraine. Alpha blockers, which counter a different set of effects, are used to treat several cardiovascular. Alpha-2 agonists often have an effect, and are commonly used as anesthesia-enhancers in surgery. Many important psychiatric drugs exert strong effects on systems in the brain. Norepinephrine is a catecholamine and a phenethylamine and its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word normal, norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. These amino acids are found in nearly every protein and, as such, are provided by ingestion of protein-containing food, phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the tyrosine hydroxylase, with tetrahydrobiopterin, O2. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, dopamine is then converted into norepinephrine by the enzyme dopamine β-monooxygenase, with O2 and ascorbic acid as cofactors. Norepinephrine itself can further be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as cofactor, in mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the monoamine oxidase or COMT

28.
Reuptake
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Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake. The first primary sequence of a protein was published in 1990. After separation, it was realized that there were similarities between the two DNA sequences. The members of new family include transporters for dopamine, norepinephrine, serotonin, glycine, proline. They were called Na+/Cl− dependent neurotransmitter transporters, Sodium and Chloride ion dependence will be discussed later in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family, in addition to this, the N- and C-termini exist in the intracellular space. These proteins also all have an extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labeling experiments verified the predicted topological organization of the serotonin transporter, in addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter, Sodium Symporters. They found that the transmembrane helices 1 and 6 contained unwound segments in the middle of the membrane, along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites. The crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6-10, there is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position, external and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8. The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron, typical neurotransmitter sodium symport transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane. The ions flow down their concentration gradients, in many cases leading to transmembrane charge movement that is enhanced by the membrane potential and these forces pull the neurotransmitter substrate into the cell, even against its own concentration gradient. At a molecular level, Na+ ions stabilize amino acid binding at the substrate site, the role of the Cl− ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na+. After ion and substrate binding have taken place, some conformational change must occur and this increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the system in question, a reuptake inhibitor can have drastic effects on cognition. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of inhibitors in the extracellular permeation pathway

29.
Alcoholic beverage
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Long-term use can lead to alcohol abuse, physical dependence, and alcoholism. Drinking alcohol plays an important social role in many cultures, most countries have laws regulating their production, sale, and consumption, some countries ban such activities entirely. However, alcoholic drinks are legal in most parts of the world, the global alcoholic drink industry exceeded $1 trillion in 2014. Alcohol is one of the most widely used drugs in the world. For instance, in 2015, among Americans, 89% of adults had consumed alcohol at point, 70% had drunk it in the last year. Alcoholic drinks are divided into three classes—beers, wines, and spirits—and typically contain between 3% and 40% alcohol by volume. Discovery of late Stone Age jugs suggest that intentionally fermented drinks existed at least as early as the Neolithic period, wine is a fermented beverage produced from grapes. Wine involves a longer process than beer and also a long aging process. Sparkling wine can be made by means of a secondary fermentation, fruit wines are made from fruits other than grapes, such as plums, cherries, or apples. Sake is an example of rice wine. Beer is a beverage fermented from grain mash and it is made from barley or a blend of several grains. If the fermented mash is distilled, then the drink is a spirit, beer is the most consumed alcoholic beverage in the world. Cider or cyder is an alcoholic drink made from any fruit juice, apple juice, peaches. Cider alcohol content varies from 1. 2% ABV to 8. 5% or more in traditional English ciders, in some regions, cider may be called apple wine. Mead is a drink created by fermenting honey with water, sometimes with various fruits, spices, grains. The alcoholic content of mead may range from about 8% ABV to more than 20%, the defining characteristic of mead is that the majority of the drinks fermentable sugar is derived from honey. A distilled drink or liquor is a drink produced by distilling ethanol produced by means of fermenting grain, fruit. Unsweetened, distilled, alcoholic drinks that have a content of at least 20% ABV are called spirits

30.
1-(3-Chlorophenyl)piperazine
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Meta-Chlorophenylpiperazine is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as ecstasy in Europe, despite its advertisement as a recreational substance, mCPP is actually generally considered to be an unpleasant experience and is not desired by drug users. It lacks any reinforcing effects, produces depressive and anxiogenic effects in rodents and humans and it also worsens obsessive-compulsive symptoms in people with the disorder. MCPP is known to induce headaches in humans and has used for testing potential antimigraine medications. It has potent anorectic effects and has encouraged the development of selective 5-HT2C receptor agonists for the treatment of obesity as well. MCPP possesses significant affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and it also has some affinity for α1-adrenergic, α2-adrenergic, H1, I1, and NET. It behaves as an agonist at most or all serotonin receptors, MCPP has been shown to act not only as a reuptake inhibitor of serotonin but as a releasing agent as well. MCPPs strongest actions are at the 5-HT2B and 5-HT2C receptors and its discriminative cue is mediated primarily by 5-HT2C, however, there is also evidence for mCPP antagonism of the 5-HT2A receptor, suggesting an indirect mechanism for the drugs psychedelic effects. Other effects of mCPP include nausea, hypoactivity, and penile erection, MCPP is metabolized via the CYP2D6 isoenzyme by hydroxylation to p-hydroxy-mCPP. Caution should be exercised in coprescribing inhibitors or substrates of CYP2D6 with drugs such as trazodone and nefazodone that have mCPP as a metabolite, as of October 2015 mCPP is a controlled substance in China. MCPP is legal in the Czech Republic, MCPP is illegal in Hungary since 2012. MCPP is illegal in Japan since 2006, MCPP is not illegal in the Netherlands. An amnesty for possession and usage of these remained until October 2008. However, it is important to note that mCPP is legally used for scientific research, chlorophenylpiperazine is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess in Florida. Quipazine - A related piperazine serotonin agonist

Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of

1.
Methylphenidate, in the form of Ritalin pills.

Misuse of Drugs Act 1975
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The Misuse of Drugs Act 1975 is a New Zealand drug control law that classifies drugs into three classes, or schedules, based on their projected risk of serious harm of loss of life. The Controlled Substances Classification system has been around for decades but only in 2006 was benzylpiperazine was classified that a substance first became scheduled

1.
Misuse of Drugs Act 1975

PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be dow

1.
PubChem

ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The

1.
ChemSpider

Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of

1.
Al 2 (SO 4) 3

International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL lic

1.
L - ascorbic acid

Recreational drug
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Recreational drug use is the use of a psychoactive drug to alter ones mental state in a way that modifies emotions, perceptions, and feelings for recreational purposes. When a substance enters the body, it brings on an intoxicating effect. Generally, people use drugs that fall into three categories, depressants, stimulants, and psychedelic drugs. I

1.
Adriaen Brouwer 's The Smokers, circa 1636

2.
The Drinkers by Jean Béraud, c. 1908

3.
Martini, a popular cocktail, containing alcohol a common depressant

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Cappuccino, a coffee drink containing caffeine a popular stimulant

Piperazine
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Piperazine is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste, the piperazines are a broad class of chemical compounds, many with important pharmacological properties, which contain a core piperazin

Structural analog
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It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analog can be imagined to be formed, at least theoretically, despite a high chemical similarity, structural analogs are not necessarily functional analogs and can have very different physical, chemical

1.
A mechanical network diagram of a simple resonator (top) and one electrical network with an equivalent structure and behaviour (bottom), then, an analog for it.

Benzylpiperazine
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Benzylpiperazine is a recreational drug with euphoriant and stimulant properties. The effects produced by BZP are comparable to those produced by amphetamine, adverse effects have been reported following its use including acute psychosis, renal toxicity and seizures. No deaths have been reported following a sole ingestion of BZP and its sale is ban

1.
A selection of products containing BZP.

3.
Typical pupil dilation

4.
An impure ' ecstasy ' tablet – seized by law enforcement in the United States – containing BZP, methamphetamine, and caffeine

MDMA
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3, 4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a psychoactive drug used primarily as a recreational drug. Desired effects include increased empathy, euphoria, and heightened sensations, when taken by mouth, effects begin after 30–45 minutes and last 3–6 hours. It is also sometimes snorted or smoked, as of 2017, MDMA has no accept

1.
Ecstasy is commonly consumed at raves. Above, a rave in Austria in 2005.

4.
A salt of MDMA (typically white) with impurities, resulting in a tan discoloration

Affinity (pharmacology)
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In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein, the binding typically results in a change of conformation of the target protein. In DNA-ligand

5-HT1A
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The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin. It is a G protein-coupled receptor that is coupled to Gi/Go, HTR1A denotes the human gene encoding for the receptor. The 5-HT1A receptor is the most widespread of all the 5-HT receptors, the 5-HT1A receptors in the raphe nucleus are largely somat

1.
5-hydroxytryptamine (serotonin) receptor 1A, G protein-coupled

5-HT1B
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5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype, 5-HT1B receptors are widely distributed throughout the CNS with the highest concentrations found in the frontal cortex, basal ganglia, striatum, and the hippocampus. The function

1.
5-hydroxytryptamine (serotonin) receptor 1B, G protein-coupled

5-HT1D
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5-hydroxytryptamine receptor 1D, also known as HTR1D, is a 5-HT receptor, but also denotes the human gene encoding it. 5-HT1D acts on the nervous system, and affects locomotion. It also induces vascular vasoconstriction in the brain, 5HT1D receptor is a G protein linked receptor that activates an intracellular messenger cascade to produce an inhibi

1.
5-hydroxytryptamine (serotonin) receptor 1D, G protein-coupled

5-HT2A
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The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an effect on certain areas such as the visual cortex. This receptor was first noted for its impo

1.
5-hydroxytryptamine (serotonin) receptor 2A, G protein-coupled

2.
Chromosome 13.

5-HT2C
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The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin. It is a G protein-coupled receptor that is coupled to Gq/G11, HTR2C denotes the human gene encoding for the receptor, that in humans is located at the X chromosome. As males have one copy of the gene and in one of the two copies of the gene is re

1.
5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled

Receptor (biochemistry)
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In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, however, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporte

Full agonist
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An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist, receptors can be activated by either endogenous or exogenous agonists, resulting in a biological response. A physiological agonist is a substance that cre

Receptor antagonist
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A receptor antagonist is a type of receptor ligand or drug that blocks or dampens agonist-mediated responses rather than provoking a biological response itself upon binding to a receptor. They are sometimes called blockers, examples include alpha blockers, beta blockers, antagonist activity may be reversible or irreversible depending on the longevi

1.
Antagonists will block the binding of an agonist at a receptor molecule, inhibiting the signal produced by a receptor-agonist coupling.

Meta-chlorophenylpiperazine
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Meta-Chlorophenylpiperazine is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as ecstasy in Europe, despite its

5-HT3
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This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to sodium, potassium, and calcium ions. Binding of the neu

1.
Figure 1. The subunits are assembled as a pentamer (right) and each subunit has four transmembrane domains (left).

Serotonin transporter
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The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of transporter protein that transports serotonin from the synaptic cleft to the presynaptic neuron. This transport of serotonin by the SERT protein terminat

1.
Slc6a4 is expressed in median and dorsal raphe in the midbrain of the postnatal day 56 mouse. Allen Brain Atlases

2.
Solute carrier family 6 (neurotransmitter transporter), member 4

Releasing agent
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Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e. g. trace amines, many substituted amphetamines, and related compounds. MRAS can be classified by the monoamines they mainly release, although these drugs like on a spectrum and they may enter the presynaptic neuron primarily via plasma membra

1.
Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine.

Serotonin
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Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is found in the gastrointestinal tract, blood platelets. It is popularly thought to be a contributor to feelings of well-being, approximately 90% of the human bodys total serotonin is located in the enterochromaffin cells in the GI tra

1.
Serotonin

Dopamine
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Dopamine is an organic chemical of the catecholamine and phenethylamine families that plays several important roles in the brain and body. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, dopamine is also synthesized in plants and most multicellular animals. In the brain, dopamine functions a

Norepinephrine
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Norepinephrine, also called noradrenaline or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone and neurotransmitter. Norepinephrine is also the international nonproprietary name given to the drug, regardless of which name is used for the substance itself, parts of the body that produc

1.
Norepinephrine

Reuptake
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Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, much research, both biochemical and structural, has been performed

1.
A synapse during re-uptake. Note that some neurotransmitters are lost and not reabsorbed.

Alcoholic beverage
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Long-term use can lead to alcohol abuse, physical dependence, and alcoholism. Drinking alcohol plays an important social role in many cultures, most countries have laws regulating their production, sale, and consumption, some countries ban such activities entirely. However, alcoholic drinks are legal in most parts of the world, the global alcoholic

1.
A selection of alcoholic beverages.

2.
A liquor store in the United States. The global alcoholic beverages industry has exceeded $1 trillion in 2014.

1-(3-Chlorophenyl)piperazine
–
Meta-Chlorophenylpiperazine is a psychoactive drug of the phenylpiperazine class. It was initially developed in the late-1970s and used in scientific research before being sold as a drug in the mid-2000s. It has been detected in pills touted as legal alternatives to illicit stimulants in New Zealand and pills sold as ecstasy in Europe, despite its

1.
St. Augustine is the oldest city in the U.S., established in 1565 by Spain.

2.
Flag

3.
Aerial view of Castillo De San Marcos (Florida).

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The five flags of Florida from the right, Spain (1565–1763), the Kingdom of Great Britain, Spain (1784–1821), the Confederacy, and the United States. France (flag not shown) also controlled part of Florida.